Tetherin (BST-2 or CD317) is an interferon-inducible transmembrane protein that inhibits virus release from infected cells. Whereas most simian immunodeficiency viruses (SIVs) use Nef to overcome restriction by tetherin in their non-human primate hosts, the Vpu protein of HIV-1 and the Env protein of HIV-2 have evolved to serve this function in humans due to the absence of sequences in the cytoplasmic domain of human tetherin that confer susceptibility to Nef. We recently identified compensatory changes in the gp41 tail that restore resistance to tetherin in a nef-deleted strain of SIV that regained a pathogenic phenotype in rhesus macaques. These observations are analogous to the adaptation of HIV-2 Env for antagonism of human tetherin and imply that resistance to tetherin is important for lentiviral pathogenesis. We have now identified HIV-1 Nef alleles that are able to counteract restriction by human tetherin, further underscoring the extraordinary plasticity of the primate lentiviruses in adapting to the tetherin proteins of their respective hosts and revealing a previously unappreciated role for Nef in HIV-1 infection. The studies outlined in this proposal seek to advance our understanding of the mechanisms of lentiviral resistance to tetherin and their role in immunodeficiency virus infection. The first objective of this proposal (Aim 1) is to define the molecular interactions and cellular trafficking pathways involved in SIV Nef antagonism of rhesus tetherin.
This aim will build on work by our group identifying Nef as the viral gene product of SIV that antagonizes restriction by tetherin to determinie the nature of the molecular interactions between Nef and tetherin and the fate of tetherin in SIV-infected cells. Our second objective (Aim 2) is define the genetic changes associated with the gain of anti-tetherin activity by HIV-1 Nef and the mechanism by which HIV-1 Nef counteracts human tetherin. These studies are important for determining how widespread this activity of Nef is among primary HIV-1 isolates, the circumstances that lead to tetherin antagonism by HIV-1 Nef, and the mechanistic differences in tetherin antagonism by HIV-1 Nef versus SIV Nef. Our third objective (Aim 3) is to assess the natural variation in anti-tetherin activity for primary HIV-2 En proteins and to define the sequences in Env required for this activity. These studies will reveal the prevalence/range of anti-tetherin activity for primary HIV-2 Env proteins and the molecular adaptations in Env that contribute to this activity. By comparing the activity of Env alleles derived from individuals with progressive courses of HIV-2 infection to Env alleles derived from asymptomatic individuals who contain virus replication, these studies may also reveal whether differences in tetherin antagonism are related to differences in HIV-2 pathogenesis.
Tetherin (BST-2 or CD317) is a component of innate immunity that inhibits virus release from infected cells. The studies in this proposal will advance our understanding of the mechanisms of HIV and SIV resistance to tetherin. A better understanding of the mechanisms used by AIDS viruses to counteract tetherin will be important for the development of novel antiretroviral drugs to enhance the susceptibility of HIV to tetherin.
|Banerjee, Priyankana; Ries, Moritz; Janaka, Sanath Kumar et al. (2018) Diversification of Bw4 Specificity and Recognition of a Nonclassical MHC Class I Molecule Implicated in Maternal-Fetal Tolerance by Killer Cell Ig-like Receptors of the Rhesus Macaque. J Immunol 201:2776-2786|
|Richard, Jonathan; Prévost, Jérémie; von Bredow, Benjamin et al. (2017) BST-2 Expression Modulates Small CD4-Mimetic Sensitization of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity. J Virol 91:|
|Arias, Juan F; Colomer-Lluch, Marta; von Bredow, Benjamin et al. (2016) Tetherin Antagonism by HIV-1 Group M Nef Proteins. J Virol :|
|Bimber, Benjamin N; Evans, David T (2015) The killer-cell immunoglobulin-like receptors of macaques. Immunol Rev 267:246-58|
|Schafer, Jamie L; Ries, Moritz; Guha, Natasha et al. (2015) Suppression of a Natural Killer Cell Response by Simian Immunodeficiency Virus Peptides. PLoS Pathog 11:e1005145|
|Gardner, Matthew R; Kattenhorn, Lisa M; Kondur, Hema R et al. (2015) AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature 519:87-91|
|Hölzemer, Angelique; Thobakgale, Christina F; Jimenez Cruz, Camilo A et al. (2015) Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa. PLoS Med 12:e1001900; discussion e1001900|
|Pomplun, Nicholas; Weisgrau, Kim L; Evans, David T et al. (2015) OMIP-028: activation panel for Rhesus macaque NK cell subsets. Cytometry A 87:890-3|
|Scull, Margaret A; Shi, Chao; de Jong, Ype P et al. (2015) Hepatitis C virus infects rhesus macaque hepatocytes and simianized mice. Hepatology 62:57-67|
|von Bredow, Benjamin; Arias, Juan F; Heyer, Lisa N et al. (2015) Envelope Glycoprotein Internalization Protects Human and Simian Immunodeficiency Virus-Infected Cells from Antibody-Dependent Cell-Mediated Cytotoxicity. J Virol 89:10648-55|
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